Infants dying with persistent pulmonary hypertension of the newborn (PPHN) have distal lung arteries with remarkably thickened walls which obstruct blood flow, thereby contributing to death. The thickening results from both proliferation of the smooth muscle with extension into the smallest vessels, and from increased production of adventitial matrix proteins such as collagen and elastin. We propose that because the lung circulation is still developing at birth, insults such as hypoxia and mechanical stress will cause unique responses resulting in rapid and excessive thickening of arterial walls. In particular, receptor expression, intracellular signalling pathways, and constitutive and/or induced nuclear gene expression are expected to be unique in newborns. Based on our preliminary results, we focus on the growth factors IGF-1 and TGF-beta as related to smooth muscle cells and fibroblasts. The proposal utilizes fluids and (when available) tissue from PPHN patients, an animal model with severe pulmonary hypertension (the newborn calf at high altitude), cultured whole pulmonary arteries, and cell cultures. We expect that better understanding of the mechanisms of arterial wall thickening will lead to more effective prevention and treatment of PPHN.